1. Update on Therapies: Clinical Trials Timothy PM Whelan Assistant Professor of Medicine Medical Director, Interstitial Lung Disease Program University of Minnesota

2. Outline Pathogenesis of pulmonary fibrosis Targets of treatment Measuring safety and efficacy of Rx Recent and current clinical trials Summary University of Minnesota

3. Pulmonary Fibrosis Scarring of the lungs produced by collagen deposition Once scar is well established, disrupts normal architecture of the lung Result: oxygen from the air does not transfer into the blood stream normally University of Minnesota

4. Microscopic injury to the lung Focal fibroblast proliferation Collagen deposition Return of normal lung architecture Normal Lung Repair Dissolution of the scaffolding University of Minnesota

5. Dissolution of the scaffolding Persistence of collagen scar Microscopic injury to the lung Focal fibroblast proliferation Collagen deposition Abnormal transfer of oxygen into the blood stream Cause of Pulmonary Fibrosis Recurrent microscopic injury University of Minnesota

6. Treatment Options Stop the cycle of recurrent injury Avoidance of known risk factors –Occupational exposures –Tobacco –Organic and inorganic dust exposures –Prevent infections: influenza, pneumococcus Treatment of medical conditions associated with development of fibrosis University of Minnesota

7. Treatment Options Stop continued deposition of collagen Affect mechanisms known to activate the fibroblast Increase removal of fibroblasts Boost the immune system? University of Minnesota

8. Treatment Options There are no proven medical therapies for the treatment of Idiopathic Pulmonary Fibrosis Future successful treatment relies on well designed clinical trials University of Minnesota

9. Clinical Trials Research protocols in human subjects Designed to answer a specific question Observational Trials Large groups of people in natural setting Interventional Trials Investigate experimental treatment effects Several phases or steps in drug development University of Minnesota

10. Phase I A new drug or treatment tested in a small group of people for the first time evaluate its safety determine a safe dosage range identify side effects may include healthy subjects University of Minnesota

11. Phase II Controlled clinical studies Evaluate the effectiveness of the drug for a particular indication or indications Tested in patients with the disease or condition under study Determine the common short-term side effects and risks. University of Minnesota

12. Phase III Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug gather additional information to evaluate the overall benefit-risk relationship of the drug provide an adequate basis for physician labeling University of Minnesota

13. Phase IV Post-marketing studies Delineate additional information including the drug's risks, benefits, and optimal use. University of Minnesota

14. Trial Design Basics Hypothesis Primary versus secondary endpoints “Power” Ability of study to determine a difference Assumptions made by researchers –Number of patients enrolled –Number of events that are expected to occur –Estimation of treatment effect of intervention University of Minnesota

15. Trial Design Basics Inclusion criteria Specific disease process Age, test results, symptoms Exclusion criteria Concomitant illnesses Known interactions with interventions University of Minnesota

16. Trial Design Basics Control Group Placebo Inactive compound Current standard regimen University of Minnesota

17. Benefits Well-designed and well-executed clinical trials allow eligible participants to: Play an active role in their own health care. Gain access to new research treatments before they are widely available. Obtain expert medical care at leading health care facilities during the trial. Help others by contributing to medical research. www.clinicaltrials.gov University of Minnesota

18. Risks There may be unpleasant, serious or even life-threatening side effects to experimental treatment. The experimental treatment may not be effective for the participant. The protocol may require more of their time and attention than would a non-protocol treatment, including trips to the study site, more treatments, hospital stays or complex dosage requirements. www.clinicaltrials.gov University of Minnesota

19. Trial Design Basics Informed Consent Process by which study participants are fully informed as to specific risks/benefits of a particular protocol Process does not stop once enrolled but continues throughout the study period Consent within a study is voluntary and can be withdrawn at any point University of Minnesota

20. Clinical Investigations - IPF Phase I FG-3019 – completed Phase II Bosentan (Tracleer ® ) – enrollment closed Etanercept (Enbrel ® ) – enrollment closed Imatinib (Gleevec ® ) – enrollment ongoing Pirfenidone – completed Phase III Gamma Interferon-1b (Actimmune ® ) -- ongoing University of Minnesota

21. Summary Pulmonary fibrosis results from the normal healing process going astray Treatment options once pulmonary fibrosis develops are limited Clinical trials involve multiple phases of investigation University of Minnesota

22. Summary Multiple promising drug therapies are already under investigation Well designed, large clinical trials are the key to obtaining answers for the future University of Minnesota

23. Resources to learn more www.clinicaltrials.gov www.coalitionforpf.org www.thoracic.org/patiented/patedmaterials.asp www.lungusa.org University of Minnesota Center for Advanced Lung Disease Registry of Interested Persons University of Minnesota

24. Resources to learn more University of Minnesota Center for Advanced Lung Disease Registry of Interested Persons Contact Jenny or Joslyn: (612) 625-7741 Toll Free: 1-800-646-9255 E-mail: bieveØØ3@umn.edu University of Minnesota